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Patients with Chronic Granulomatous Disease Have a Reduced Peripheral Blood Memory B Cell Compartment¹

Jack J. Bleesing^2,*, Margarida M. Souto-Carneiro^,, William J. Savage, Margaret R. Brown^¶, Cynthia Martinez^¶, Sule Yavuz, Sebastian Brenner, Richard M. Siegel, Mitchell E. Horwitz, Peter E. Lipsky, Harry L. Malech and Thomas A. Fleisher^¶

^* Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; Instituto Gulbenkian de Ciência, Oeiras, Portugal; Autoimmunity Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and ^¶ Department of Laboratory Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892

In this study, we have identified an altered B cell compartment in patients with chronic granulomatous disease (CGD), a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH activity. This is characterized by an expansion of CD5-expressing B cells, and profound reduction in B cells expressing the memory B cell marker, CD27. Both findings were independent of the age, genotype, and clinical status of the patients, and were not accompanied by altered CD5 and CD27 expression on T cells. Focusing on CD27-positive B cells, considered to be memory cells based on somatically mutated Ig genes, we found that the reduction was not caused by CD27 shedding or abnormal retention of CD27 protein inside the cell. Rather, it was determined that CD27-negative B cells were, appropriately, CD27 mRNA negative, consistent with a naive phenotype, whereas CD27-positive B cells contained abundant CD27 mRNA and displayed somatic mutations, consistent with a memory B cell phenotype. Thus, it appears that CGD is associated with a significant reduction in the peripheral blood memory B cell compartment, but that the basic processes of somatic mutation and expression of CD27 are intact. X-linked carriers of CGD revealed a significant correlation between the percentage of CD27-positive B cells and the percentage of neutrophils with normal NADPH activity, reflective of the degree of X chromosome lyonization. These results suggest a role for NADPH in the process of memory B cell formation, inviting further exploration of secondary Ab responses in CGD patients.

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